The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2 enzymes.
Leukotrienes and prostaglandins are important mediators of inflammation, each of which classes contributes to the development of an inflammatory response in a different way. Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the cxtravasation of these cells and stimulate release of superoxide and proteases which damage the tissue. Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science, 237:1171-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli.
Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized [W. L. Smith, Biochem. J., 259;315-324 (1989)] from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of COX-1 and COX-2 enzymes. Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes.
Arachidonic acid which is fed into these two distinct inflammatory pathways is released from the sn-2 position of membrane phospholipids by phospholipase A2 enzymes (hereinafter PLA2). The reaction catalyzed by PLA2 is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of PLA2 is of the phospholidyl choline class with an ether linkage in the sn-1 position, the lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation [S. I. Wasserman, Hospital Practice, 15:49-58 (i988)].
Most anti-inflammatory therapies have focussed on preventing production of either prostglandins or leukotrienes from these distinct pathways, but not on all of them. For example, ibuprofen, aspirin, and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX-1/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways. Conversely, zileuton inhibits only the pathway of conversion of arachidonic acid to leukotriense, without affecting the production of prostaglandins. None of these widely-used anti-inflammatory agents affects the production of PAF.
Consequently the direct inhibition of the activity of PLA2 has been suggested as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory response. [See, e.g., J. Chang et al, Biochem. Pharmacol., 36:2429-2436 (1987)].
A family of PLA2 enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined. These secreted PLA2s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA2s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated.
The primary structure of the first human non-pancreatic PLA2 has been determined. This non-pancreatic PLA2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme. This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem., 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem., 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophys. Res. Comm., 163:42-48 (1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-pancreatic PLA2 is an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic pathways for these compounds are intracellular proteins. Moreover, there is evidence that PLA2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme.
A murine PLA2 has been identified in the murine macrophage cell line, designated RAW 264.7. A specific activity of 2 mols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta., 963:476-492 (1988)]. The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA2.
A cytosolic phospholipase A2 (hereinafter xe2x80x9ccPLA2xe2x80x9d) has also been identified and cloned. See, U.S. Pat. Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth. The enzyme of these patents is an intracellular PLA2 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
Now that several phospholipase enzymes have been identified, it would be desirable to identify chemical inhibitors of the action of enzymes, which inhibitors could be used to treat inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are all desired results. There remains a need in the art for an identification of such anti-inflammatory agents for therapeutic use in a variety of disease states.
SUMMARY OF THE INVENTION
Compounds of this invention have the following formulae: 
wherein:
R1 and R1, are independently selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, or xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH; or R1 and R1, are a moiety of the formulae: 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C(O)CH3, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C5 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, adamantyl, or morpholinyl, xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)n-O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94(Oxe2x80x94CH2-phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94COOH, xe2x80x94CF3,CO2H, or xe2x80x94OH;
n is an integer from 0 to 3;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, xe2x80x94CF3, xe2x80x94COOH, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkylxe2x80x94C3-C10 cycloalkyl, xe2x80x94CHO, halogen, or a moiety of the formulae: 
wherein n is independently selected in each appearance as an integer from 0 to 3, preferably 0 to 2, more preferably 0 to 1, Y is C1-C6 alkyl, C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, morpholinyl, pyrrolidinyl, or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O;
R4 is selected from the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C6 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94C1-C5 cycloalkyl, or the groups of:
A) xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, or a moiety of the formulae: 
wherein n is independently selected in each appearance as an integer from 0 to 3, preferably 0 to 2, more preferably 0 to 1, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
b) a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl, pyrimidinyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, or xe2x80x94NO2; or
c) a moiety of the formulae: 
wherein Z is O or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, or xe2x80x94NO2; or
d) a moiety of the formula xe2x80x94L2xe2x80x94M2, wherein:
L2 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)C(O)X;
where Xxe2x95x90O,N
M2 is selected from the group of C1-C5 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
i) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
ii) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
iii) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
n is an integer from 0 to 3;
R5 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, (CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)n-tetrazole, xe2x80x94CH2-phenyl-C(O)-benzothiazole, 
or a moiety selected from the formulae xe2x80x94L1xe2x80x94M1;
wherein L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94,xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94Oxe2x80x94;
M1 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
where R8, R9 or R10 can be attached anywhere in the cyclic or bicyclic system, n is an integer from 0 to 3;
R8, in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
R9 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
n is an integer from 0 to 3;
R10 is selected from the group of H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1xe2x80x94C6 alkyl, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2, 
n is an integer from 0 to 3;
R11 is selected from H, C1-C6 lower alkyl, C1-C6 cycloalkyl, xe2x80x94CF3, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, 
with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R5, R8, R9, R10, and/or R11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
or a pharmaceutically acceptable salt thereof.
One preferred subset of the compounds of this invention, as defined above, are those having the formulae: 
Compounds within this invention have the following formulae: 
wherein:
R1 and R1, are independently selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH; or a moiety of the formulae: 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94OH, xe2x80x94CF3, C1-C5 alkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, xe2x80x94CN, C1-C6 alkyl, C1-C5 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CF3, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2,xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, xe2x80x94CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkyl-C3-C10 cycloalkyl, xe2x80x94CHO, halogen, or a moiety of the formula xe2x80x94L2xe2x80x94M2:
L2 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)n xe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)C(O)X;
where Xxe2x95x90O,N
M2 is selected from the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
n is an integer from 0 to 3;
R4 is selected from the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C6 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, or the groups of:
a) xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2phenyl)2, xe2x80x94CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae; 
wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
b) a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, or xe2x80x94NO2; or
c) a moiety of the formulae: 
wherein Z is O or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, or xe2x80x94NO2;
R5 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)n-tetrazole, 
or a moiety selected from the formulae xe2x80x94L1xe2x80x94M1;
wherein L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(C2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94,xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)n xe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94, or xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2,xe2x80x94(CH2)nxe2x80x94;
M1 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
where R8, R9 or R10 can be attached anywhere in the cyclic or bicyclic system,
R8, in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
R9 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
R10 is selected from the group of H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2, 
R11, is selected from H, C1-C6 lower alkyl, C1-C6 cycloalkyl, xe2x80x94CF3, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, 
with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R5, R8, R9, R10, and/or R11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: 
n is an integer from 0 to 3;
or a pharmaceutically acceptable salt thereof.
It will be understood in the group above that substituents R3 and R4 are bound to the indole or indoline ring""s 2- or 3-position and the R1, R1, and R2 groups are bound to one of the indole or indoline ring""s 4-, 5-, 6- or 7-position carbon atoms.
One group of compounds within this invention are those in which the R1, and R3 groups are hydrogen and the substituents at the other indole or indoline positions are as described above.
Another group of this invention comprises compounds in which the R1, and R3 groups are hydrogen and the groups at R1, R4, and R5 are as defined above. Within this group are two further preferred groups. In the first, R1 is in the indole or indoline 5-position and in the second R1 is in the indole or indoline 6 position.
In a further preferred group herein, R1 is in the indole or indoline 5-position and is benzyloxy, R2 and R4 are hydrogen and R3 and R5 are as defined above.
In an another preferred group of this invention R1 is in the indole or indoline 5 or 6 position and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino, R2 and R4 are hydrogen, and R3, and R5 are as defined above.
A further preferred group of this invention consists of R1 and R2 at the indole or indoline 5 and or 6 position and are each selected from the group consisting of C1-C6alkoxy, cyano, sulfonyl and halo, R2 and R4 are hydrogen, and R3 and R5 are as defined above.
It is also understood that there is a further preferred subgroup within each of the groups set forth herein wherein the core molecule is an indole moiety, rather than an indoline. There is also understood to be a second group within each wherein the core molecule is an indoline moiety.
A Preferred Group of Compounds of this Invention Have the Following Formulae 
wherein:
R1 and R1, are independently selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
or R1 and R1, are independently a moiety of the formulae: 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94C(O)CH3 phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl,xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, adamantyl, or morpholinyl, xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3,CO2H, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, xe2x80x94CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkyl, xe2x80x94C3-C10 cycloalkyl, xe2x80x94CHO, halogen, (CH2)nC(O)NH2 or a moiety of the formula xe2x80x94L1xe2x80x94M1:
L1 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, C(O)C(O)X, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(CH2)n 
M1 is selected from:
a) H, the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
R4 is selected from the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C6 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, or the groups of:
a) a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl, pyrimidinyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, or xe2x80x94NO2; or
b) a moiety of the formula xe2x80x94L2xe2x80x94M2, wherein:
L2 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)C(O)X;
where Xxe2x95x90O,N
M2 is selected from the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3 C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
i) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
ii) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
iii) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH;
n is an integer from 0 to 3;
R5 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, (CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)n-tetrazole, xe2x80x94CH2-phenyl-C(O)-benzothiazole, or 
or a moiety selected from the formulae xe2x80x94L3xe2x80x94M3;
wherein L3 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O)xe2x80x94C(Z)xe2x80x94N(R6)xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94C(Z)xe2x80x94NHxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
M3 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
where R8, R9 or R10 can be attached anywhere in the cyclic or bicyclic system,
n is an integer from 0 to 3;
R8 in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
R9 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
n is an integer from 0 to 3;
R10 is selected from the group of H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nC(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)2, 
n is an integer from 0 to 3;
R11 is selected from H, C1-C6 lower alkyl, C1-C6 cycloalkyl, xe2x80x94CF3, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, 
with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R5, R8, R9, R10, and/or R11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
or a pharmaceutically acceptable salt thereof.
A Preferred Group of Compounds of this Invention Have the Following Formulae 
wherein:
R1 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1xe2x80x94C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
or R1 and R1, are independently a moiety of the formulae: 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94C(O)CH3phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl,xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, adamantyl, or morpholinyl, xe2x80x94(CH2)nxe2x80x94phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2xe2x80x94phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3,CO2H, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, xe2x80x94CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkyl, -C3-C10 cycloalkyl, xe2x80x94CHO, halogen, xe2x80x94(CH2)nC(O)NH2 or a moiety of the formula xe2x80x94L1xe2x80x94M1:
L1 indicates a linking or bridging group of the formulae xe2x80x94(CH2)n, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)Nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, C(O)C(O)X, or xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(CH2)n;
where X is O or N
M1 is selected from:
a) H, the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3 or xe2x80x94OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3or xe2x80x94OH;
R4 is selected from the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C6 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, or the groups of:
a) a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl, pyrimidinyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, or xe2x80x94NO2;
R5 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, (CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)n-tetrazole, or 
or a moiety selected from the formulae xe2x80x94L3xe2x80x94M3;
wherein L3 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
M3 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
where R8, R9 can be attached anywhere in the cyclic or bicyclic system,
n is an integer from 0 to 3;
R8, in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
R9 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
n is an integer from 0 to 3;
with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R5, R8, R9, shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
or a pharmaceutically acceptable salt thereof.
A preferred group of compounds of this invention have the following formulae: 
wherein:
R1 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
or R1 and R1, are independently a moiety of the formulae:
or a moiety of the formulae: 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94C(O)CH3 phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C1-C6 alkyl)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl,-O-phenyl, benzyl, xe2x80x94O-benzyl, adamantyl, or morpholinyl, xe2x80x94(CH2)n-phenyl-O-phenyl, xe2x80x94(CH2)n-phenyl-CH2-phenyl, xe2x80x94(CH2)nxe2x80x94O-phenyl-CH2-phenyl, xe2x80x94(CH2)n-phenyl-(Oxe2x80x94CH2-phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94CF3,CO2H, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, xe2x80x94CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, xe2x80x94C1-C6 alkyl, xe2x80x94C3-C10 cycloalkyl, xe2x80x94CHO, halogen, (CH2)nC(O)NH2 or a moiety of the formula xe2x80x94L1xe2x80x94M1:
L1 indicates a linking or bridging group of the formulae xe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, (CH2)xe2x80x94Oxe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(C2)nxe2x80x94, C(O)C(O)X,xe2x80x94(CH2)nxe2x80x94Nxe2x80x94(C2)n;
M1 is selected from:
a) H, the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, or xe2x80x94CF3; or
R4 is selected from the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, xe2x80x94(CH2)nxe2x80x94C3-C6 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)xe2x80x94C3-C5 cycloalkyl, or the groups of:
a) a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl, pyrimidinyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, or xe2x80x94NO2;
R5 is selected from xe2x80x94COOH, xe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, (CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94COOH, xe2x80x94(CH2)n-tetrazole, or a moiety selected from the formulae xe2x80x94L3xe2x80x94M3;
wherein L3 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94,xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94,xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
M3 is selected from the group of xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, 
where R8, R9 can be attached anywhere in the cyclic or bicyclic system,
n is an integer from 0 to 3;
R8, in each appearance, is independently selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, tetrazole, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
R9, is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
n is an integer from 0 to 3;
with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R5, R8, R9, shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: xe2x80x94C(O)xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NH2, 
n is an integer from 0 to 3;
or a pharmaceutically acceptable salt thereof.
This invention further comprises compounds having the following formulae: 
wherein:
R1 and R1, are independently selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH; or R1 and R1, are independently a moiety of the formulae: 
R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R7 is selected from xe2x80x94OH, xe2x80x94CF3, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NHxe2x80x94(C1-C6 alkyl), xe2x80x94Nxe2x80x94(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, xe2x80x94O-phenyl, benzyl, xe2x80x94O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, xe2x80x94CN, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CF3, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94(CH2)xe2x80x94OH, (CH2)nC(O)NH2, xe2x80x94CH2xe2x80x94Oxe2x80x94(C1-C6 alkyl, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl, xe2x80x94CH2xe2x80x94Nxe2x80x94(C1-C6 alkyl), xe2x80x94CH2xe2x80x94Nxe2x80x94CH2-phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, xe2x80x94CF3 or xe2x80x94C1-C6 alkyl;
X is O or N
n=0 or 1;
R4 is a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy or xe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, or xe2x80x94NO2;
R5 is a moiety selected from the groups of: 
wherein L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94(CH2)nxe2x80x2xe2x80x94,xe2x80x94(CH2)nxe2x80x2xe2x80x94Sxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94SOxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94;
where nxe2x80x2 is an integer from 0 to 5;
R9 is selected from xe2x80x94CF3, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2,
n in each instance is independently selected as an integer from 0 to 3;
or a pharmaceutically acceptable salt thereof.
This invention comprises compounds having the following formulae: 
wherein:
R1 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C10 alkyl, preferably xe2x80x94Sxe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, benzyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, xe2x80x94C1-C1 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94(CH2)xe2x80x94OH, (CH2)nC(O)NH2, xe2x80x94CH2xe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl, xe2x80x94CH2xe2x80x94Nxe2x80x94(C1-C6 alkyl), xe2x80x94CH2xe2x80x94Nxe2x80x94CH2-phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, xe2x80x94CF3 or xe2x80x94C1-C6 alkyl;
n=0 or 1.
R4 is a moiety of the formulae xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, wherein A is the moiety: 
wherein
D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or xe2x80x94CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, or xe2x80x94NO2;
R5 is a moiety selected from the groups of: 
wherein L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94,xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
where n=0-5
R9 is selected from xe2x80x94CF3, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2,
n in each instance is independently selected as an integer from 0 to 3
or a pharmaceutically acceptable salt thereof
This invention comprises compounds having the following formulae: 
wherein:
R1 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94HN(C1-C6), xe2x80x94N(C1-C6)2, phenyl, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, xe2x80x94(CH2)xe2x80x94OH, (CH2)nC(O)NH2, xe2x80x94CH2xe2x80x94Oxe2x80x94(CH1-C6 alkyl), xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl, xe2x80x94CH2xe2x80x94Nxe2x80x94(C1-C6 alkyl), xe2x80x94CH2xe2x80x94Nxe2x80x94CH2-phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, xe2x80x94CF3 or xe2x80x94C1-C6 alkyl;
n=0 or 1.
R5 is a moiety selected from the groups of: 
wherein L1 is a bridging or linking moiety selected from a chemical bond, xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94C(O)xe2x80x94(CH2nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94(CH2)nxe2x80x2xe2x80x94,xe2x80x94(CH2)nxe2x80x2xe2x80x94Sxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94SOxe2x80x94(CH2)nxe2x80x2xe2x80x94, xe2x80x94(CH2)nxe2x80x2xe2x80x94SO2xe2x80x94(CH2)nxe2x80x2xe2x80x94, or xe2x80x94(CH2)nxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x2xe2x80x94Oxe2x80x94; 
nxe2x80x2 in each instance is independently selected as an integer from 0 to 5;
or a pharmaceutically acceptable salt thereof.
It is also understood that there is a further preferred subgroup within each of the groups set forth herein wherein the core molecule is an indole moiety, rather than an indoline. There is also understood to be a second group within each wherein the core molecule is an indoline moiety.